Ergoline dimers

ABSTRACT

Substituted ergolines are dimerized under acidic conditions to yield compounds useful as sunscreen agents.

United States Patent 1 Bach et al.

111 3,880,856 51 Apr. 29, 1975 ERGOLINE DlMERS [75] Inventors: Nicholas J. Bach; Edmund C.

Kornfeld, both of Indianapolis. Ind.

[73] Assignee: Eli Lilly and Company. Indianapolis,

Ind,

221 Filed: June 29. 19-13 2! Appl. N0.;37s,212

OTHER PU BLICATIONS Morrocchi et 21].. Chemical Abstracts Vol. 69, 77248u I968.

Kubbe et al., Chemical Abstracts, Vol. 74. l4l0l8b. 1971.

Primary Examiner-Donald G. Daus Assistant E.\'aminer-Mary C. Vaughn Arturney, Agent, or Firm-James L. Rowe; Everet F. Smith [57] ABSTRACT Substituted ergolines are dimerized under acidic conditions to yield compounds useful as sunscreen agents.

7 Claims, No Drawings ERGOLINE DIMERS BACKGROUND OF THE INVENTION Compounds based on the ergoline ring system:

have a surprising variety of pharmaceutical activities. For example. lysergie and isolysergic acid are 8-carboxy-6-methyl-A -ergolines. The amides of lysergic acid. many of which have valuable and unique pharmacologic properties. include the naturally occurring oxytocic alkaloids ergocornine. ergokryptine. ergonovine. ergocristine. ergosine. ergotamine etc. and synthetic oxytocics such as methergine as well as the synthetic hallucinogen lysergic acid diethylamide or LSD. The amides of 6methyl-8-carboxyergoline. known generically as dihydroergot alkaloids. are oxytocic agents of lower potency and also lower toxicity than the ergot alkaloids themselves. Recently. it has been found by Clemens. Semonsky. Meites, and their various coworkers that many ergot-related drugs have activity as prolactin inhibitors including ergocornine. dihydroergocorine. 2-bromoa-ergokryptine and d-6-methyl-8- cyanomethylergoline. References embodying some of the newer findings in the field of ergoline chemistry are the following: Nagasawa and Meites. Prue. Soc. Exp. Biol. Med. l35. 469 (I970); Lutterbeck et al.. Brit. Med. J.. 228. (July, 24. l97l Heuson et al.. Europ. J. Cancer. 353 (i970); C011. (:ech. Chem. Commun.. 33. 577 (1968); Nature. 221. 666 (1969); Seda et al.. J. Reprod. For! 24. 263 (1971); Mantle and Finn. id. 441'. Semonsky and co-workers. Coll. Czech. Chem. Cumm.. 36. 2200 (l97l Schaar and Clemens. Enducn. 90, 285-8 (1972); and Clemens and Schaar. Proc. Soc. Exp. Biol Med.. 139. 659-662 (l972). Recently issued patents in the field of ergoline derivatives or lysergic acid derivatives include the following: U.S. Pat. No. 3.704.233. U.S. Pat. No. 3.709.891. U.S. Pat. No. 3,585.20l. U.S. Pat. No. 3.666.762. U.S. Pat. No. 3.586.683. U.S. Pat. No. 3.717.640. and U.S. Pat. No. 3,592.8]6.

No instance ofdimeric ergoline compounds has been found in the prior art.

SUMMARY OF THE INVENTION This invention provides dimeric ergoline compounds of the formula and the A A and A derivatives thereof wherein R is carbo-lower-alkoxy. lower alkyl. chloromethyl. hydroxymethyl. cyanomethyl. and N-carboxamido methyl (-CH C-NH or the A A and N derivatives thereof wherein R has the same meaning as above. The fi-methyl ergolines and the A A and A derivatives thereof represented by Formula II upon treatment with acid are smoothly converted to the corresponding dimer of Formula I. The dimeric products produced thereby are isolated from the reaction mixture by routine chemical procedures. Acids useful in causing the dimerization include Lewis acids of the type. phosphorusoxychloride. trifluoroacetic acid. boron trifluoride etherate. phosphorus pentachloride. polyphosphoric acid and the like.

The compounds of this invention absorb ultra violet light in the region from about 200 p. to 300 a. As such they are useful as sun screen agents in that they will protect fabrics and the like from harmful effects of ultraviolet radiation when incorporated thereon as a surface coating. For example. the dimer from A ""-6- methyl-8 carbomethoxyergoline absorbs ultraviolet light strongly in the region from 200-230 a and from 280-3l0 p. with peak absorption at 295 a. The dimer prepared from the corresponding A"""- ergoline has a marked ultraviolet absorption in the region 260-230 [.L. The dimer prepared from A 6.8-dimethylergoline absorbs ultraviolet light chiefly in the region 200-230 1. as does the dimer prepared from 6-methyl-8 cyanomethylergoline. The compounds are in general soluble in polar organic solvents such as the lower alcohols and can be applied to the surface to be protected from the harmful effects of ultraviolet radiation as an alcoholic solution.

The preparation of the compounds of this invention is illustrated by the following specific example.

EXAMPLE residual dimeric product from methanol yielded the h dimer of methyl 9,10-dihydrolysergate (formula 1 above in which R is carbomethoxy) which melted at about 242245 C. with decomposition after recrystallization from methanol.

Analysis Calc. for C H,,,N O

Requires: C, 71.81; H, 7.09; N, 9.85;

Found: C, 71.64; H, 7.19; N, 9.98. Other compounds prepared by the above procedure include the following: Dimer prepared from A "-6-methyl-8-carbomethoxyergoline (Formula I wherein R is carbomethoxy and with a double bond between the 9 and 10 positions) not crystallineanalytical sample precipitated from etherhexane; mp. slow dec 150 C.

Analysis ca1c1C, 72.32; H 6.43; N, 9.92; O, 11.33.

Found: C, 72.48; H, 6.55; N, 9.98; 0, 11.26. The dimer prepared from A -(rmethyl-8-carbomethoxyergoline (Formula 1 having a double bond between the 7 and 8 carbons and a carbomethoxy group at 8). Not crystallineanalytical sample precipitated from ether-hexane; infra red, ultraviolet, molecular ion and nmr spectra all support the projected structure.

Analysis calc:

C, 72.32; H, 6.43; N, 9.92; O, 11.33.

Found: C, 71.39; H. 6.85; N, 9.34; O, 11.91. The dimer from A -6,8 dimethylergoline (Formula 1 which R is metyl and there is a double bond between the 8 and 9 carbons) not crystalline-analytical sample precipitated from ether-hexane mp=slow dec 150 C.

Analysis calc: C, 80.63; H, 7.61; N, 11.75;

Found: C, 80.80; H, 7.73; N. 12.03. The dimer from fi-methyl-8-hydroxymethylergoline (Formula I in which R is -CH.,OH). The dimer from 6 -methyl-8-cyanomethylergoline (formula 1 wherein R is CH CN) crystallized from methanol; mp=2268 dec. Infra-red, ultraviolet, molecular ion and nmr spectra support the postulated structure.

Analysis calc: C, 76.95; H, 7.27; N, 15.84; Found: C, 75.28; H, 6.82, N, 15.26. The dimer from 6-methyl8-chloromethylergoline (Formula I wherein R is CH CI); crystallized from methanol; mp=slow dec 175C.

Analysis calc: C, 69.93; H, 6.97; N, 10.19; Cl, 12.90;

Found: C, 69.72; H, 6.74; N, 10.24; Cl, 13.00.

Other compounds preparable by the above procedure include the dimer from 6-methyl-8-carbox amidomethylergoline (Formula I wherein R is H CH C-Nl l the dimer from 6methyl-8-ethylergoline (Formula 1 wherein R is ethyl); the dimer from A -6-methyl-8-npropylergoline (Formula I wherein R is n-propyl and there is a double bond between the 9 and 10 carbon atoms); the dimer from 66 -6-methyl-8-carboethoxyergoline (Formula I wherein R is carboethoxy and there is a double bond between the 9 and 10 carbon atoms); the dimer from 6-methyl-8 carboisopropoxyergoline (Formula 1 wherein R is carboisopropoxy); the dimer from A -6-methyl8-chloromethylergoline (Formula 1 wherein R is CHgCl and there is a double bond between the 7 and 8 carbon atoms); the dimer from other A -ergo1ines can be prepared from the corresponding 8-substituted ergoline derivative by the above procedure.

The starting materials useful in preparing the monomers of formula ll above are well known where the formula discloses ergolines (dihydrolysergic acid structure) and their A and A derivatives. The A"'" ergolines are, however, new compounds and are prepared readily according to the following procedure in which the preparation of A -l-isopropyl-6-methyl-8- carbomethoxyergoline is exemplified. In the procedure, an N-oxide is formed on the C nitrogen by means of peroxybenzoic acid. Decomposition of the N oxide by triethylamine followed by acetic anhydride yields the desired A""' derivative.

A solution of 3.26 g. of methyl l-isopropyl dihydrolysergate was prepared in 50 m1. of chloroform. A second solution containing 2.10 g. of m-chloroperbenzoic acid in 35 ml. of chloroform was added in dropwise fashion over a 20 minute period. The mixture was stirred for about one half a hour and then 2.0 ml. of triethylamine were added followerd by the dropwise addition of ml. of acetic anhydride over a minute period. The temperature of the reaction mixture rose to about 40 C. The reaction mixture was stirred for one-half hour further after which time 50 ml. of water were added followed by an excess of 14 N aqueous ammonium hydroxide. A -l-isopropyl-6-methyl-S-carbomethoxyergoline residue which readily crystallized from methanol. A l-isopropyl-6-methyl-8-carbomethoxyergoline thus prepared melted at about l82-3 C. A -ergolines without a substituent an the indole nitrogen are prepared similarly.

We claim:

I. A compound according to the following formula wherein R is carbomethoxy. carboethoxy carbo-npropoity carboisopropoxy methyl, ethyl, n-propyl, isopropyl, hydroxyrnethyl, chloromethyl, or cyanomethyl, and the A A and A""" derivatives thereof.

2. Compound according to claim 1, said compound being the dimer from A""" -6-methyl-8-carbomethoxyergoline.

3. Compound according to claim 1, said compound being the dimer from A -6-methyl-8-carbomethoxyergoline.

4. A compound according to claim I. said compound being the dimer from A"'' -6.8-dimethylergoline.

5. A compound according to claim I, said compound being the dimer from 6-methyl-8-cyanornethylergoline.

6. The process of preparing a compound of the following structure or A A8(9). and A derivatives thereof wherein R is carbomethoxy, carboethoxy, carbo-npropoxy, carboisopropoxy, methyl, ethyl. n-propyL isopropyl, hydroxymethyl. chloromethyl, or cyanomethyl which comprises the steps of reacting a compound of the structure acetic acid. 

1. A COMPOUND ACCORDING TO THE FOLLOWING FORMULA
 2. Compound according to claim 1, said compound being the dimer from Delta 7(8) -6-methyl-8-carbomethoxyergoline.
 3. Compound according to claim 1, said compound being the dimer from Delta 9(10) -6-methyl-8-carbomethoxyergoline.
 4. A compound according to claim 1, said compound being the dimer from Delta 8(9) -6,8-dimethylergoline.
 5. A compound according to claim 1, said compound being the dimer from 6-methyl-8-cyanomethylergoline.
 6. The process of preparing a compound of the following structure or Delta 7(8), Delta 8(9), and Delta 9(10) derivatives thereof
 7. The process according to claim 6 wherein the Lewis acid is borontrifluoride etherate in trifluoroacetic acid. 